The Inherited Bone Marrow Failure Syndromes (IBMFS) are a group of rare clinical disorders that include Fanconi anemia (FA), dyskeratosis congenita (DKC), Schwachman-Diamond syndrome (SDS), congenital amegakaryocytic thrombocytopenia, and others. Many of these disorders are associated with abnormal telomere maintenance (DKC being the most severe) which can be a valuable diagnostic screening tool but is also likely linked to development of the immunodeficiency observed in some patients. We have recently identified a number of patients in our Immunodeficiency clinic who actually have various forms of IBMFS but presented with immune deficiency up to 20 years before other, more classic symptoms of IBMFS disorders became apparent. Unfortunately, the spectrum of immune deficiency observed in these disorders has not been systematically evaluated and the consequences of abnormal telomere maintenance on lymphocyte development in humans has only partially been explored. Our long-term goal is to understand how profound immune deficiency develops in the setting of inherited bone marrow failure disorders. The objectives of this application are to determine the incidence of bone marrow failure (screening for abnormal telomere maintenance) among patients with humoral immunodeficiency and to better define the humoral immunodeficiency observed in patients with defined bone marrow failure syndromes. The central hypothesis of the application is that in the absence of functional telomerase, there is a progressive decline in the telomeres of immune cells as they develop, leading to a progressive loss of mature cells and subsequent immunodeficiency. This hypothesis has been formulated based on clinical experience and preliminary data as well as on published reports. The rationale for the proposed research is our recent identification of patients with IBMFS who have profound immunodeficiency that pre-dated the appearance of other symptoms typically associated with bone marrow failure. We plan to test our central hypothesis and accomplish the objective of this application by pursuing the following specific aims: 1) Determine the incidence of telomere shortening in patients with Common Variable Immunodeficiency (CVID) and Combined Immune Deficiency (CID), and 2) Evaluate B cell development and maturation in patients with defined bone marrow failure syndromes. The proposed work is innovative because it approaches the question of the association between bone marrow failure and immunodeficiency from both sides and utilizes advanced flow cytometric assays to evaluate patient samples. This will offer the most complete assessment of the association between IBMFS and immunodeficiency to date. PUBLIC HEALTH RELEVANCE: The inherited bone marrow failure syndromes are a group of rare disorders in which patients develop low blood counts because of decreased production or survival of one or more blood cell lines. Immune abnormalities have been described in some of these patients however the specific immune defects associated with the more common bone marrow failure syndromes have not been systematically evaluated. This project seeks to evaluate the link between inherited bone marrow failure syndromes (particularly those associated with shortened telomeres) and immune deficiency.